2. Academic Validation
  3. Trajectory modeling of endothelial-to-mesenchymal transition reveals galectin-3 as a mediator in pulmonary fibrosis

Trajectory modeling of endothelial-to-mesenchymal transition reveals galectin-3 as a mediator in pulmonary fibrosis

  • Cell Death Dis. 2021 Mar 26;12(4):327. doi: 10.1038/s41419-021-03603-0.
Wangyue Jia  # 1 2 3,  Zhaoyan Wang  # 1 2 3,  Ceshu Gao  # 4,  Jian Wu 5,  Qiong Wu 6 7
Affiliations

Affiliations

  • 1 MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, China.
  • 2 Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China.
  • 3 Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China.
  • 4 Department of Neurology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China.
  • 5 Department of Neurology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China. wujianthu@mail.tsinghua.edu.cn.
  • 6 MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, China. wuqiong@mail.tsinghua.edu.cn.
  • 7 Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China. wuqiong@mail.tsinghua.edu.cn.
  • # Contributed equally.
PMID: 33771973 DOI: 10.1038/s41419-021-03603-0
Abstract

The endothelial-to-mesenchymal transition (EndMT) is an important source of fibrotic cells in idiopathic pulmonary fibrosis (IPF). However, how endothelial cells (ECs) are activated and how EndMT impact IPF remain largely elusive. Here, we use unsupervised pseudotemporal analysis to recognize the heterogeneity of ECs and reconstruct EndMT trajectory of bleomycin (BLM)-treated Tie2creER/+;Rosa26tdTomato/+ IPF mice. Genes like C3ar1 and Lgals3 (protein name Galectin-3) are highly correlated with the transitional pseudotime, whose expression is gradually upregulated during the fate switch of ECs from quiescence to activation in fibrosis. Inhibition of Galectin-3 via siRNA or protein antagonists in mice could alleviate the pathogenesis of IPF and the transition of ECs. With the stimulation of human pulmonary microvascular endothelial cells (HPMECs) by recombinant proteins and/or siRNAs for Galectin-3 in vitro, β-catenin/GSK3β signaling and its upstream regulator Akt are perturbed, which indicates they mediate the EndMT progress. These results suggest that EndMT is essential to IPF process and provide potential therapeutic targets for vascular remodeling.

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